Compositions and methods for t cell delivery of therapeutic molecules

A modified T cell comprising a nucleic acid encoding a soluble fusion protein, wherein the soluble fusion protein comprises a first binding domain comprising an anti-CD28 scFv and a second binding domain comprising an anti-PD-L1 or anti-TGFbRII scFv.

A modified T cell comprising a nucleic acid encoding a switch molecule and at least one of nucleic acid encoding soluble fusion protein and a nucleic acid encoding a bispecific antibody, wherein the T cells transiently expresses the switch molecule and secretes the soluble fusion protein and/or the bispecific antibody.

A method for delivering a factor to a target site, the method comprising:

• administering a population of cells to a subject in need thereof, wherein the T cells transiently express a switch molecule, wherein the switch molecule comprises an extracellular domain comprising a transforming growth factor-beta receptor (TGF-beta-R) or fragment thereof and an intracellular domain comprising a IL-12R or fragment thereof, and
• wherein interaction of the extracellular domain of the switch molecule with its respective ligand induces the T cells to secrete an activation factor at the target site.

A method for delivering a factor to a target site, the method comprising:

• administering a population of cells comprising T cells to a subject in need thereof, wherein the T cells home to the target site and transiently express a switch molecule comprising an extracellular domain comprising a membrane receptor or fragment thereof and an intracellular domain comprising a signaling receptor or fragment thereof and a bispecific antibody comprising bispecificity for an antigen on a target cell and an antigen on an activating T cell;
• and
• activating the T cells at the target site, wherein the T cells are induced to secrete an activation factor.

A method of treating a disease or condition comprising administering to a subject a population of modified T cells comprising a nucleic acid encoding a switch molecule comprising an extracellular domain comprising a membrane receptor or fragment thereof selected from the group consisting of a cytokine receptor, a chemokine receptor, a growth factor receptor, a hormone receptor, and other signaling receptor;

• and an intracellular domain comprising a signaling receptor or fragment thereof, and wherein the T cells transiently express the switch molecule and interaction of the extracellular domain of the switch molecule with its respective ligand induces the T cells to secrete an activation factor at the target site, thereby treating the disease or condition.

A method of treating a disease or condition comprising administering to a subject a population of modified T cells comprising a nucleic acid encoding a switch molecule comprising an extracellular domain comprising a membrane receptor or fragment thereof and an intracellular domain comprising a signaling receptor or fragment thereof and at least one of a nucleic acid encoding soluble fusion protein and a nucleic acid encoding a bispecific antibody comprising bi specificity for an antigen on a target cell and an antigen on an activating T cell, and wherein the T cells transiently express the switch molecule and soluble fusion protein and/or bispecific antibody and activation of the T cells induces secretion of an activation factor at the target site, thereby treating the disease or condition.

A method for generating a T cell transiently expressing a switch molecule comprising:

• introducing a nucleic acid encoding a switch molecule into a population of T cells, wherein the switch molecule comprises an extracellular domain comprising a membrane receptor or fragment thereof selected from the group consisting of a cytokine receptor, a chemokine receptor, a growth factor receptor, a hormone receptor, and other signaling receptor, or an extracellular domain comprising a signaling receptor or fragment thereof;
• and an intracellular domain comprising a signaling receptor or fragment thereof, and wherein the T cells transiently express the switch molecule and interaction of the extracellular domain of the switch molecule with its respective ligand induces the T cells to secrete an activation factor at a target site, thereby generating the T cell.

A method for generating a T cell transiently expressing a switch molecule and bispecific antibody comprising:

• introducing a nucleic acid encoding a switch molecule comprising an extracellular domain comprising a membrane receptor or fragment thereof and an intracellular domain comprising a signaling receptor or fragment thereof and at least one of a nucleic acid encoding a soluble fusion protein and a nucleic acid encoding a bispecific antibody comprising bispecificity for an antigen on a target cell and an antigen on an activating T cell, and wherein the T cells transiently express the switch molecule and soluble fusion protein and/or bispecific antibody and activation of the T cells induces secretion of an activation factor at a target site.